At present a large part of the population of babies in industrialised countries are fed with specialised infant formulae. It has been reported that consumption of these formulae is associated with several medical problems, such as increased frequency of gastrointestinal problems and decreased immune status. Such problems may occur at young age, but perhaps also at later age, because infants that are exclusively fed with human breast milk would score better on these parameters. It has also been reported that infants that are exclusively fed with these artificial formulae suffer from longer episodes of crying compared to those that are fed with human breast milk. This suggests a general feeling of discomfort due to perhaps hunger, pain or even medical problems. These problems may delay development of the child and produce concerns and practical problems to the parents.
In a first aspect of the invention it is aimed to develop a new infant formula for complete nutrition that decreases the number of crying episodes and promotes sleeping behaviour for the child, especially for infants of young gestational age.
In a second aspect it is also aimed to develop infant formulae that compensate for the relatively small capacity of the (rapidly developing) metabolic systems of the child shortly after birth. This leads to improved health, formation of higher quality new tissue (visual acuity, intellectual capacities, etc.), a better immune status and a decrease in occurrence of periods of increased bilirubin plasma levels (hyperbilirubinaemia or jaundice). Increased bilirubin levels are known to occur relatively often within the first 3 weeks after birth. Some of the negative effects of this disorder have been described in the prior art, including the inhibition by bilirubin of the uptake of the neurotransmitters dopamine and glutamate by the synaptic vesicles and the neurotoxic effects that this disease state may have.
Conventional infant formulae have been developed that mimic the composition of human breast milk to a degree that can be achieved at a reasonable price. These formulae are normally based on cow's milk proteins like casein or mixtures of casein and whey. In case of problems, such as metabolic disorders or allergic reactions, other protein sources are used like hydrolysates or soybean proteins; alternatively the allergic component is replaced by another non-allergenic ingredient. However, the composition of these formulae still differs from that of human breast milk. The relatively low levels of tryptophan and cysteine/cystine can be compensated for by increasing the amount of protein in the product. However, this increases the amount of threonine to very high levels and increases the costs of the formulae. Also the imbalances with regard to the ratio of tryptophan to the sum of the large neutral amino acids will be maintained.
In a further aspect, the invention is related to the use of folic acid, and at least one of vitamin B12 and B6, or their functional analogues in the manufacture of compositions for the prevention and/or treatment of specific neurological disorders. The invention also covers the products that are obtained by such use. Products according to the invention will be effective in improving sleep behaviour, insomnia and mood, in decreasing feelings of fear, pain, restlessness and depression and increasing feelings of wellbeing. In addition, these symptoms as related to neurodegenerative disorders like Alzheimer, Parkinson and schizophrenia will decreas, though the disease itself is not cured. Also, the products can be helpful in the prevention and/or treatment of the symptoms that are typically associated with restless legs syndrome, myoclonus (a disorder that is often accompanied by muscle contractions and seizures), Gilles de la Tourette, Carpal tunnel syndrome, phenyl-ketonuria, multiple sclerosis, analgesia, epilepsy, mania, ADHD, and psychiatric disorders associated with ageing. Relatively large parts of the population suffer from one of these disorders. Application of common drug therapy may result in undesired side effects, such as addiction and gradual loss of effectivity, and may lead to functional deficiencies of food components. So there is a need for a pharmaceutical or nutritional formulation that helps prevent or treat these disorders and does not result in these side effects.
Sandyk, R., reported in Intern. J Neuroscience, 1992, 67, 127-144 that several, but not all, of these disorders were associated with decreased serotonin levels in the brain and reviewed some of the relevant literature about the use of tryptophan to restore serotonin levels in the brain.
In a next aspect of the invention the products according to the invention aim to improve sleep behaviour, insomnia and mood, in decreasing feelings of fear, pain, restlessness and depression and increasing feelings of well-being during many immune-related diseases. Immune-related diseases are diseases, in which the recognition of cells is hampered or disturbed and thus results in an inappropriate reaction against undesired cells or antigens. Examples of such diseases are several infectious diseases and cancers in which too weak of a reaction occurs against mutated or infected cells and many autoimmune diseases, in which relatively mild antigens trigger a disproportional strong reaction.
In U.S. 2002/0155104 such an imparted tryptophan metabolism is recognized in cells that are infected by specific viruses. By influencing the activity of indoleamine 2,3-dioxygenase (IDO), in particular by administering inhibitors of IDO, '104 aims to decrease or increase tryptophan levels to levels below or above physiological levels. The beneficial effects of protein composition or vitamins are not contemplated.
The inventors theorize that during all the immune-related diseases as mentioned above local tryptophan homeostasis is significantly disturbed. By mutated or infected cells, eg those infected by HIV, cytomegalovirus and Herpes, significant amounts of cytokines will be released which increase tryptophan catabolism significantly. The increase in tryptophan catabolism also decreases systemic plasma tryptophan levels and increases at least locally levels of kynurenine, and their metabolites like quinolinates, kynurenates, anthranilates and niacin or nicotinamide. Also formate is released and endogenous local levels of total nicotinamide nucleotides (predominantly the sum of NAD+, NADP+, NADPH and NADH) as well as serotonin are decreased. Such disturbances of total tryptophan metabolism, which includes serotonin and melatonin homeostasis leads to a locally and strongly compromised immune function, especially against infected and mutated cells of the body, which could result in metastasis or rapid tumor growth and rapid infection rates and thus leads to fatigue, decreased stamina, anorexia and increased feelings of pain.
Also in so called autoimmune diseases, like rheumatoid arthritis, Crohn's Disease, diabetes type 1, lupus erythematosus, multiple sclerosis, scleroderma, psoriasis, etc, total tryptophan metabolism appears to be imparted. In these situations tryptophan catabolism does not function as an appropriate inhibitor of the antigenic reaction. Endogenous and exogenous products, which are recognized as antigens therefore trigger a very strong response, which includes itching, sensations of burning, pressure, and varying degrees of pain, changing from vague pain to smarting—and aggressive pains. Food and non-food allergies may also result in a wide range of systemic reactions which include diarrhoea, airway obstruction and even shock. In autoimmune diseases, dependant on the nature of the disease, a gradual destruction of tissue may be observed, as well as several symptoms that are typical for the autoimmune disease.
The inventors further consider that these disorders are associated not only with a disorder in serotonin levels, but also with the melatonin levels in the brain, the presence of pterines and folate in the brain and the functioning of tryptophan metabolism and the methylating system in the body. The latter may become evident by abnormal systemic and local adenosine and/or tryptophan levels. Because relatively very little serotonin or melatonin is present in the normal diet, most endogenous amounts must originate from biosynthesis. An increase in the brain levels of both serotonin and melatonin can therefore only be achieved by increasing the metabolic capacity of the serotoninergic neurons. An increase of the brain levels of both serotonin and melatonin and the presence of reduced folic acid and pterins in the brain would lead to a relief of the clinical problems.
Sandyk disclosed that in some cases administration of an effective amount of the natural precursor of serotonin, tryptophan, could lead to increased levels of serotonin in brain tissue. This idea was also subject of a number of other publications, which appeared in the past.
WO 87/01590 (=EP-A-238533, Kreitzman) discloses a slimming diet for adults that provides per day less than 1000 kcal (so less than 14 kcal/kgbw.d; less than 700 kcal/day is preferred), less than 100 g protein (which results in less than 1.4 g protein per kgbw per day for a 70 kg person; always more than 30 g and less than 46 g protein is preferred) and more than 0.5 g tryptophan (more than 3 g is preferred). The product is unsuitable for feeding infants due to too high protein levels and potential toxicity of the amount of tryptophan that is included. The product should also not be used for combating obesity of the infant.
EP-A-007691 (Wurtman) discloses a formula for suppression of appetite for carbohydrates in adults, which comprises tryptophan, in an amount of 10-100 mg per kgbw.d, and carbohydrates, but no branched-chain amino acids. The ratio of the amounts of tryptophan and carbohydrates in the formula must be 1: 3-50. The product is unsuitable for use in infants, because infants require branched chain amino acids at young age for growth.
U.S. Pat. No. 5,053,429 (Hirsch) discloses a method for treating pain in a subject comprising administering to the subject in dosage form an effective relieving amount of at least one specific methionine compound, the unnatural d-isomer which does not occur in proteins, and optionally at least one of 0.3-30 ug vitamin B12, 0.2-20 mg vitamin B6 and 40-4000 ug folic acid. The methionine compound is administered in an amount of 1.0-10 g per 70 kg body weight.
Juma reviewed in Schmerz 1998, 12, 136-141 the analgesic properties of B-vitamins. Administration of very high doses of each of specific B-vitamins (20-200 mg vitamin B1 resulted in a “trend”; 100-500 mg vitamin B6 during carpal tunnel syndrome or 5-10 mg vitamin B12 during osteoarthritis resulted in an analgesic effect, though others have criticised the research that has been done on the role of vitamin B6 in carpal tunnel syndrome) or in combination (100-300 mg vitamin B1, 100-600 mg vitamin B6 and 0.6-1 mg vitamin B12 per day during diabetic neuropathies) resulted in an analgesic effect. Chronic administering of such high dose of vitamin B6 was found to damage neurons. Folic acid and proteins were not considered.
WO 91/10441 (=EP-A-463154) discloses compositions comprising polypeptides containing more than 2.2% tryptophan as well as arginine or omithine for providing a “serotinergic effect”. The product is developed for combating obesity in adults and treating feelings of depression. Preferably α-lactalbumin is used as a source of tryptophan, which possesses a high ratio of tryptophan to large neutral amino acids plus methionine. Vegetable proteins are suggested as attractive ingredients, because of their relatively high amount of arginine and relatively low levels of phenylalanine and tyrosine. The latter two amino acids are however essential amino acids and recommended daily intakes should be ensured.
WO 98/14204 discloses the use of α-lactalbumin as nutritional complement or medicine for regulating sleep, especially when a jet lag is observed. Consumption of 100 mg and 250 mg α-lactalbumin is claimed to be effective in adults. No relation is made to use in infants nor is indicated that vitamins might play a role in regulating sleep. Alpha-lactalbumin was shown to have a value of the ratio of tryptophan to the sum of the large neutral amino acids is about 0.074 and that of the ratio Cys to Trp equals about 1.47, while the amount of tryptophan is relatively high (about 3.0%).
Heine discloses the use of hydrolysed α-lactalbumin as protein source in infant formulae in DE-A-4130284. Use of this protein hydrolysate was claimed in order to achieve a clear separation with β-lactoglobulin and thus administer a better-balanced composition with regard to threonine, tryptophan and cysteine/cystine. No reference was made to specific positive effects that can be obtained by using intact α-lactalbumin with regard to feelings of well-being nor the support of insufficiently functioning metabolic systems by using the products of the invention. No indication is given that folic acid, vitamin B12 and B6 play a crucial role in these respects. The products disclosed by Heine are also more expensive and have a worse taste compared to the products of the present invention.
After consumption of carbohydrates, insulin is released from the pancreas. This latter component is known to reverse the catabolic processes in the body, that may have resulted from a period of starvation prior to the (re)feeding of the child, into anabolic processes. As long as sufficient glucose is present in the plasma, plasma insulin levels remain sufficiently high to prevent catabolism of (in particular muscle) tissue and the resulting release of branched chain amino acids (BCAA, valine, isoleucine and leucine). In a further aspect, the invention is therefore aimed at developing formulae that provide an insulin response on a short term, with a sufficient longer-term effect as well.
Infants, especially those of young gestational age, are extremely sensitive to consumption of excess amounts of food components and imbalances in the consumption pattern of these components, predominantly due to their relatively low metabolic and clearance capacity. This is caused by inherited problems and immaturity of their enzymatic systems and the small capacity of their organs. Infants are also sensitive to imbalances in neurotransmitter levels in the brain. It is therefore dangerous to transfer concepts that are developed for healthy adults to infant formulae. The composition of human breast milk is therefore mostly taken as “golden standard”. In another aspect of the invention, a nutritional product is aimed at that does not cause any toxic reactions in normal use and to deviate as little from the golden standard as is justified.
It is important to recognise that all the aspects as mentioned above must be achieved at the same time, in order to improve well-being satisfactorily without causing negative effects to the child.
Also elderly and diseased people may suffer from an imparted metabolic capacity and especially the group having neurodegenerative disorders, and developed viral infections ot autoimmune diseases and cancer patients should not be exposed to unbalanced food.
According to the prior art, relatively high doses of tryptophan have to be administered, optionally in the relative absence of large neutral amino acids and accompanied with digestible carbohydrates, in order to see clinical benefits. This approach leads to several problems. In some patients no or very little effect is observed. Administering high doses of tryptophan may lead to undesired side-effects, especially in those patients that have a low metabolic capacity or are deficient in certain vitamins or minerals. Examples of these patients are persons that are at risk for or are suffering from diabetes mellitus or bladder cancer, persons that are subjected to drug therapy, persons suffering of renal problems, young infants and elderly persons. Also, it appeared to be very difficult to estimate for a particular person the exact requirement of tryptophan for obtaining optimal serotonin levels and it is unknown how high these desirable serotonin levels are.
It has now been found that the restoration of the patient's capacity to metabolise tryptophan to serotonin and especially melatonin, is an approach that does not demonstrate the above-mentioned disadvantages. It allows the natural mechanisms to regulate endogenous levels, without subjecting the organism to high levels of potentially toxic tryptophan.
This can be achieved by administering extra amounts of certain cofactors, at least folic acid, vitamin B12 and vitamin B6. In this situation it is often not required to supplete tryptophan; however, in those cases that persons are deficient in tryptophan, or suffer from largely increased catabolism of tryptophan administration of relatively little amounts of tryptophan already gives significant improvement of the clinical symptoms.
In cases where a patient has a limited capacity for serotonin biosynthesis, e.g. by damage to tissue that is rich in serotoninergic neurons or due to an inherited disorder, administration of cofactors appeared to increase serotonin and melatonin levels in the brain, if a certain basal level of tryptophan was available.
It was found that the cofactors of interest are at least folate, and one of vitamin B6 and vitamin B12 or their functional equivalents. In addition it may be required to administer riboflavin, thiamine and niacin, or their functional equivalents.
The biochemical roles of folate, vitamin B6 and B12 and many of their equivalents are described in the art. To the best of the knowledge of the inventors, it is nowhere described or indicated that consumption of the combination of these vitamins, in a nutritional product that comprises only natural materials like proteins and digestible carbohydrates, is crucial for prevention or treatment of pain, anorexia, itching burning and pressure, fatigue and loss of stamina in persons that are of age above 60 years or suffer from one or more diseases or disorders. It was found that the restrictions in protein and carbohydrates composition, that are present for infant formulae, necessitate the increase in these vitamins in order to have an optimal effect. It is also not earlier disclosed that inclusion of these vitamins in the amounts as claimed, significantly enlarges the group of infants that benefit from such infant formulae, especially with regard to increase of well-being, the improvement of other serotonin or melatonin-mediated disorders.
Also, the amounts of all three essential vitamins, being folic acid, vitamin B6 and B12 are insufficient in current commercial infant formulae to support biosynthesis and metabolism, including the serotonin metabolism, in the young child.